To estimate the risk of in-hospital complications after left atrial appendage closure (LAAC) in relationship with comorbidity burden.Cohort-based observational study using the US National Inpatient Sample database, 1 October 2015 to 31 December 2017. The main outcome of interest was the occurrence of in-hospital major adverse events (MAE) defined as the composite of bleeding complications, acute kidney injury, vascular complications, cardiac complications and postprocedural stroke. Comorbidity burden and thromboembolic risk were assessed by the Charlson Comorbidity Index (CCI), Elixhauser Comorbidity Score (ECS) and CHA2DS2-VASc score. MAE were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes. The associations of comorbidity with in-hospital MAE were evaluated using logistic regression models.A total of 3294 hospitalisations were identified, among these, the mean age was 75.7±8.2 years, 60% were male and 86% whites. The mean CHA2DS2-VASc score was 4.3±1.5 and 29.5% of the patients had previous stroke or transient ischaemic attack. The mean CCI and ECS were 2.2±1.9 and 9.7±5.8, respectively. The overall composite rate of in-hospital MAE after LAAC was 4.6%. Females and non-whites had about 1.5 higher odds of in-hospital AEs as well participants with higher CCI (adjusted OR (aOR): 1.19, 95% CI: 1.13 to 1.24, p<0.001), ECS (aOR: 1.06, 95% CI: 1.05 to 1.08, p<0.001) and CHA2DS2-VASc score (aOR: 1.08, 95% CI: 1.02 to 1.15, p=0.01) were significantly associated with in-hospital MAE.In this large cohort of LAAC patients, the majority of them had significant comorbidity burden. In-hospital MAE occurred in 4.6% and female patients, non-whites and those with higher burden of comorbidities were at higher risk of in-hospital MAE after LAAC.